Nearly 100 million people in the world, including approximately 57 million in Bangladesh and about 15 million in the U.S., are chronically exposed to inorganic arsenic, a Class I human carcinogen, and are at increased risk of skin and other arsenic-induced cancers?as well as cardiovascular, pulmonary and other non-malignant disorders. As part of the Columbia University Superfund Basic Research Program, we have established Health Effects of Arsenic Longitudinal Study (HEALS)?a large prospective cohort study based on individual level data among a population exposed to a wide range of inorganic arsenic (InAs) from drinking water in Araihazar, Bangladesh. Over the past five years, using a population-based sampling frame, we recruited 11,754 men and women (with >99% response rates) and collected detailed questionnaires, clinical data, and biospecimen samples from them at baseline, two years and four years after recruitment. Through a dedicated medical clinic established by Columbia University to exclusively serve the HEALS participants, we have also developed an effective mechanism of following the cohort, especially for detecting incidence and mortality of dermatological, pulmonary, and cardiovascular disorders (CVD). In this proposal, we proposed to prospectively evaluate the effects of various measures of As exposure and metabolism on: i) incidence of skin lesions and skin cancer, ii) incidence and mortality from chronic lung disorders and mortality from lung cancers, iii) incidence and mortality from CVD, iv) serum levels of the epidermal growth factor receptor (as an early biomarker of As-induced skin carcinogenesis), v) serum levels of bronchial/alveolar cell-derived antioxidant Clara cell protein 16 (as an early biomarker of As-induced chronic lung damage and carcinogenesis), and vi) carotid artery intima-medial thickness (as early preclinical marker of As-induced vascular damage). A combination of prospective cohort, case-cohort, cross-sectional and case-control study designs will be employed to address these Specific Aims in the most efficient manner. In addition to investigating these novel research questions, as in the previous funding period, the HEALS will continue to support other biomedical research projects (including Projects 1 and 4 of the proposed program). This will be the first prospective cohort study using individual level data on As exposure and metabolism, and findings from this study will be directly relevant for both research and policy issues pertaining to the health of millions of people around the world.